tbuckley/cabot-search huggingface dataset:
Abstract 1040: Blocking hypoxia-induced carbonic anhydrases 9 enhances sensibility to cisplatin of head and neck squamous carcinoma
Authors: Annachiara Sarnella, Ylenia Ferrara, Luigi Auletta, Sandra Albanese, Vincenzo Alterio, Jean-Yves Winum, Claudiu T Supuran, Laura Cerchia, Giuseppina De Simone, Antonella Zannetti
Journal: Cancer Research (2022)

Abstract The head and neck squamous carcinomas (HNSSCs) are the sixth most common cancer worldwide. Given the heterogeneous nature of HNSCC, this carcinoma results in higher resistance to chemoradiotherapy. Recent evidence highlight the importance of the hypoxic microenvironment in contributing to cisplatin resistance. Therefore, the aim of this study was to investigate the role played by hypoxia-induced protein carbonic anhydrase 9 (CA9) in supporting HNSCC cisplatin resistance. Furthermore, we purpose to investigate the ability of CA9 inhibitor, SLC-0111, a small molecule already used in Phase I clinical trial, to sensitize HNSSC cells to chemotherapy in vitro and in vivo. We analyzed the expression of CA9 in a public data set of 103 HNSCC samples and 22 oral cavity normal tissues and in two HNSSC cell lines (FaDu; SCC-011). HNSCC cells grown in 2D and 3D models under hypoxic conditions (1% O2) showed increased levels of CA9 and greater resistance to cisplatin than cells grown under normoxic conditions. The addition of CA9 inhibitor SLC-0111 to cisplatin sensitized cells to the chemotherapeutic agent and caused a reduction of colony number, spheroid formation, tumor cell, and spheroid migration and invasiveness. Furthermore, the combination therapy hampered activation of STAT3, AKT, ERK, and EMT program whereas it induced apoptosis. Notably, the combined treatment caused inhibition of tumor growth and induction of apoptosis in HNSCC subcutaneous xenografts, as assessed by high-frequency ultrasonography and fluorescent molecular tomography (FMT) with NIR-Annexin V, respectively, at a higher extent than single agents. In addition, FMT with NIR-Prosense revealed a stronger reduction of lymph nodes metastases when mice bearing orthotopic xenografts were treated with cisplatin plus SLC-0111 with respect to a single treatment. Our findings taken together demonstrate the crucial role played by CA9 in promoting cisplatin resistance in HNSCC and the efficacy of SLC-0111 to sensitize tumor cells and xenografts to chemotherapy. Citation Format: Annachiara Sarnella, Ylenia Ferrara, Luigi Auletta, Sandra Albanese, Vincenzo Alterio, Jean-Yves Winum, Claudiu T Supuran, Laura Cerchia, Giuseppina De Simone, Antonella Zannetti. Blocking hypoxia-induced carbonic anhydrases 9 enhances sensibility to cisplatin of head and neck squamous carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1040.
Abstract 2385: A prospective investigation of serum bile acids with risk of liver cancer, fatal liver disease, and biliary cancer
Authors: Zeinab Farhat, Neal D. Freedman, Joshua N. Sampson, Roni T. Falk, Jill Koshiol, Stephanie J. Weinstein, Demetrius Albanes, Rashmi Sinha, Erikka Loftfield
Journal: Cancer Research (2022)

Abstract Abstract Background: Laboratory and emerging epidemiologic data suggest that bile acids (BAs), major regulators of the gut microbiota, play an important role in liver disease and cancer etiology. However, few epidemiologic studies have comprehensively examined associations between BAs and either liver endpoints or biliary cancer. Methods: In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, we designed 1:1 matched nested case-control studies of primary liver cancer (n=247 cases), fatal liver disease (n=261 cases), and primary biliary cancer (n=92 cases). Using baseline serum collected ≤30 years prior to diagnosis or death, we measured concentrations of 15 BAs with liquid chromatography tandem mass spectrometry. We used multivariable conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) between BAs and each endpoint, accounting for multiple comparisons. Results: Comparing the highest to the lowest quartile, ten BAs were positively associated with liver cancer risk, including taurocholic (OR =4.70, 95% CI=2.51-8.78; Q-trend&amp;lt;0.0001), taurochenodeoxycholic (OR =4.61, 95% CI=2.38-8.91; Q-trend&amp;lt;0.0001), and glycocholic acid OR =4.11, 95% CI=2.11-7.99; Q-trend&amp;lt;0.0001), and 11 were positively associated with fatal liver disease risk, including taurochenodeoxycholic acid (OR =9.65, 95% CI=4.41-21.14; Q-trend&amp;lt;0.0001), taurocholic OR =7.45, 95% CI=3.70-14.97; Q-trend&amp;lt;0.0001), taurochenodeoxycholic (OR =9.05, 95% CI=4.04-20.32; Q-trend&amp;lt;0.0001), and glycocholic acid OR=6.12, 95% CI=2.84-13.77; Q-trend&amp;lt;0.0001). No significant associations were observed between BAs and biliary cancer though ORs were consistently &amp;gt;1. Conclusion: Conjugated BAs were strongly associated with increased risk of liver cancer and fatal liver disease, suggesting mechanistic links between the gut microbiota, BA signaling pathways, and liver cancer or death from liver disease. Citation Format: Zeinab Farhat, Neal D. Freedman, Joshua N. Sampson, Roni T. Falk, Jill Koshiol, Stephanie J. Weinstein, Demetrius Albanes, Rashmi Sinha, Erikka Loftfield. A prospective investigation of serum bile acids with risk of liver cancer, fatal liver disease, and biliary cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2385.
Abstract 3359: Association of Hippo signaling pathway in acute myeloid leukemia
Authors: Heejun Jang, Sungyoung Lee, Hongseok Yun, Yongil Koh, Sung-Soo Yoon
Journal: Cancer Research (2022)

Abstract The Hippo signaling pathway, also known as the Salvador-Warts-Hippo pathway, is a well-known oncogenic signaling pathway associated with organ size regulation, cell proliferation, and apoptosis. In this study, we analyzed the association of Hippo signaling pathway genes in patients with acute myeloid leukemia (AML) using whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) data. We used Seoul National University Hospital (SNUH) AML patient data (n=16) collected from December 2015 to January 2019 for analysis. Additionally, public datasets of AML patients, TCGA-LAML (n=179) and LeuceGene (n=110) were used. we performed hierarchical clustering using Hippo pathway gene expression from AML patient samples. As a result, we discovered a gene expression signature in which the expressions of tumor suppressor genes among the Hippo pathway genes were significantly decreased. We divided AML patients into the case group and the control group according to the presence or absence of the corresponding gene expression signature and attempted to identify differences in biological features between the two groups. First, in the process of comparing differences in genetic alteration, it was confirmed that the frequency of PML-RARA fusion was significantly higher in the case group. We further analyzed the data of the AML patients in the case group without PML-RARA fusion to discover other biological features. To discover the correlation between the Hippo pathway and other oncogenic signaling pathways on gene expression level, we performed a correlation analysis. As a result, it was confirmed that the expression of the Hippo pathway gene showed a high correlation with the gene expression of the Notch signaling pathway and the Myc signaling pathway in the patients of the case group. In addition, we performed DEGs analysis to find new therapeutic target candidate genes from the case group. As a result, we identified a significantly upregulated gene, LAMP5.In conclusion, we identified the gene expression signatures of the Hippo signaling pathway in AML patients. Also, we discovered a correlation between the Hippo pathway and other signaling pathways and suggested potential therapeutic candidate genes using gene expression signatures of the Hippo signaling pathway genes. And we will perform further analysis about validating therapeutic candidate genes related to the Hippo signaling pathway gene expression signature. Citation Format: Heejun Jang, Sungyoung Lee, Hongseok Yun, Yongil Koh, Sung-Soo Yoon. Association of Hippo signaling pathway in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3359.
Abstract 6139: GPR4 promotes the development of colitis-associated colorectal cancer in an experimental mouse model
Authors: Mona A. Marie, Edward J. Sanderlin, Alexander Hoffman, Li V. Yang
Journal: Cancer Research (2022)

Abstract GPR4 is a proton-sensing G protein-coupled receptor expressed in endothelial cells as well as other cell types. Endothelial cell adhesion, blood vessel permeability, leukocyte infiltration, and angiogenesis are regulated by the proinflammatory functions of GPR4. Inhibition of GPR4 ameliorates inflammatory bowel disease (IBD) in mouse models. GPR4 expression is upregulated in the intestinal tissues of IBD and colorectal cancer patients and is associated with a worse prognosis. Herein, we studied the role of GPR4 in colitis-associated colorectal cancer (CAC) by inducing CAC in GPR4 knockout (KO) and wild-type (WT) mice using azoxymethane (AOM)/dextran sulfate sodium (DSS). The severity of CAC development was higher in WT mice than GPR4 KO mice when treated with AOM/DSS. Blood vessel density was significantly higher within the tumors of WT mouse colons compared to GPR4 KO mice. GPR4 KO tumors showed a significant increase in tumor necrosis in comparison to WT tumors. Fecal blood/diarrhea score, colon shortening, and mesenteric lymph node size were aggravated in WT mice compared to GPR4 KO mice treated with AOM/DSS. Our data demonstrate that GPR4 increases intestinal inflammation and angiogenesis, enhancing tumor development in the CAC mouse model, suggesting that GPR4 inhibition may reduce the risk of developing colitis-associated colorectal cancer. Citation Format: Mona A. Marie, Edward J. Sanderlin, Alexander Hoffman, Li V. Yang. GPR4 promotes the development of colitis-associated colorectal cancer in an experimental mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6139.
Abstract 6116: Tumor immune environment in liver metastasis of colorectal cancer and its correlation with recurrence free survival
Authors: Jiamin Zhou, Weiqi Xu, Miao Wang, Siqi Zhang, Ding Zhang
Journal: Cancer Research (2022)

Abstract Introduction: The liver is a common site of metastases of colorectal cancer. Tumor infiltrating lymphocytes (TILs) play an important role in the process of colorectal cancer liver metastasis (CRCLM). A comprehensive investigation into TILs will provide more prognostic information for patients with colorectal liver metastases after liver resection. Methods: 15 CRC patients with liver metastases from our hospital were enrolled in the study. The density and percentage of the TILs [CD8+, CD3+, CD4+, CD20+, tumor associated macrophages (TAMs), dim CD56+NK, bright CD56+NK, PD-1+etc.] in the liver metastasis samples from operation were analyzed by multiplex immunofluorescence technique (3DMedcines Inc.). The level of the density and percentage of immune cells were determined by dichotomy method. The correlation between recurrence free survival (RFS) and immune cells were analyzed using the Kaplan-Meier curve and Log-rank test. Results: The existence of dim CD56+ NK cells in the stroma was associated with significant improvement in RFS (p=0.0461). The median RFS was 26.1 months (95% CI, 14.9 to 33.5) with the existence of dim CD56+ NK cells in the stroma versus 1.7 months (95% CI, -18.0 to 32.4) without dim CD56+ NK cells in the stroma. Nevertheless, dim CD56+ NK cells in the tumor-enriched segments was not significantly associated with improved outcome. The existence of bright CD56+ NK cells in the stroma was associated with significant improvement in RFS (p=0.0307) but not in the tumor-enriched segments. The median RFS was 34.6 months (95% CI, 15.0 to 35.2) with the existence of bright CD56+ NK cells in the stroma versus 7.9 months (95% CI, -5.3 to 23.1) without bright CD56+ NK cells in the stroma. However, low FoxP3+ cells in the tumor-enriched segments (p=0.0037) was significantly associated with improved outcome but not in the stroma. The median RFS was 36.5 months (95% CI, 23.1 to 40.1) with low FoxP3+ cells versus 8.2 months (95% CI, 0.5 to 21.8) with high FoxP3+ cells in the tumor-enriched segments. Low CD3+CD4+FoxP3+ cells (p=0.074) and the existence of PD-L1+CD68+ cells (p=0.0524) in the tumor-enriched segments showed a trend towards better RFS. No significant correlation was achieved for CD8+, CD3+, CD3+CD4+, CD20+, CD68+CD163+, CD68+CD163-, PD-1, PD-1+CD8+ cells either in the tumor-enriched segments nor in the stroma. Conclusion: We identified that CD56+ NK cells in stroma are associated with improved outcome in CRCLM. Nevertheless, FoxP3+ cells are associated with poor prognosis in CRCLM. Citation Format: Jiamin Zhou, Weiqi Xu, Miao Wang, Siqi Zhang, Ding Zhang. Tumor immune environment in liver metastasis of colorectal cancer and its correlation with recurrence free survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6116.
Abstract 3: Developing a translational tool for GLP-1-based therapeutic agonists in humanized GLP1R mice
Authors: Yuelei Shen, Jiawei Yao, Mostafa Kokabee, Yanan Guo, Yang BaI, Chengzhang Shang
Journal: Cancer Research (2022)

Abstract Glucagon-like peptide-1 (GLP1) is a pleiotropic hormone released from gut enteroendocrine cells following nutrient ingestion. In addition to promoting insulin secretion and inhibiting glucagon secretion, GLP1 acts via the glucagon-like peptide-1 receptor (GLP1R) to reduce gastric emptying and food intake. Therefore, development of GLP1R agonists appears to be a promising therapeutic option for type 2 diabetes. To evaluate the efficacy of GLP1 analogs in preclinical studies, Biocytogen has successfully generated a novel humanized GLP1R (B-hGLP1R) knock-in mouse line to support related drug development studies. In this mouse model, the full coding sequence of the human GLP1R gene was inserted into the mouse Glp1r gene locus. Human GLP1R mRNA expression was detected by RT-PCR in B-hGLP1R mice but not in wild-type mice. Protein expression of human GLP1R in B-hGLP1R mice was confirmed by western blot analysis and immunohistochemistry using pancreatic tissues. Furthermore, flow cytometry analysis of leukocyte subpopulations showed that B-hGLP1R mice do not exhibit a change in the overall development, differentiation, or distribution of immune cell types in the spleen, blood, and lymph nodes. Additionally, our in vivo efficacy study confirmed Dulaglutide, a GLP1 receptor agonist, reduced the non-fasting blood glucose, fasting blood glucose, glucagon, and food intake levels in B-hGLP1R obese mice and increased plasma insulin and GLP1 secretion. In B-hGLP1R mice, glucose tolerance (GTT) was also improved by Dulaglutide treatment, similar GTT results were observed after treatment with PF-06882961, a phase II agent specifically recognizing human GLP1R. Altogether, B-hGLP1R mice provide an efficacious preclinical animal model to evaluate novel GLP1 based therapeutic drugs. Keywords: Humanized mice, GLP1R, agonist Citation Format: Yuelei Shen, Jiawei Yao, Mostafa Kokabee, Yanan Guo, Yang BaI, Chengzhang Shang. Developing a translational tool for GLP-1-based therapeutic agonists in humanized GLP1R mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3.
Abstract 2025: Spatial transcriptomic profiling of progression markers in clear cell renal cell carcinoma
Authors: Chia-Kuei Mo, Yige Wu, Terekhanova Nadezhda, Caravan Wagma, Preet Lal, Siqi Chen, Nataly Naser AL Deen, Ruiyang Liu, Yanyan Zhao, Kazuhito Sato, Lijun Yao, Mamatha Serasanambati, Andrew Shinkle, Reyka G. Jayasinghe, Li Ding, Feng Chen
Journal: Cancer Research (2022)

Abstract Next-generation sequencing enabled molecular landscaping and the discovery of novel tumor markers in ccRCC. However, the spatial relationships and histological features of the tumor microenvironment were lost during this process. Combining snRNA-seq, snATAC-seq, Spatial Transcriptomics (ST) technology, and immunofluorescence labeling, we discovered novel ccRCC progression tumor markers, and uncovered their spatial dependent expression pattern in both human ccRCC tumors and patient-derived xenograft (PDX). Using snRNA-seq and snATAC-seq, novel tumor progression markers such as NDRG1, MGST1, ABCC3 and PCSK6 were discovered, and their expressions were validated in ST. We found that one of the key novel tumor markers, CP, exhibited specific spatial expression patterns on tissue slides. The elevation of CP expression region is associated with a higher degree of hyalinization in ccRCC human tumor samples. Similarly, using immunofluorescence labeling, we validated the co-expression of CP and PCSK6 canonical ccRCC marker CA9. Overall, this study revealed novel ccRCC progression markers and linked their spatial expression pattern with histological features. Citation Format: Chia-Kuei Mo, Yige Wu, Terekhanova Nadezhda, Caravan Wagma, Preet Lal, Siqi Chen, Nataly Naser AL Deen, Ruiyang Liu, Yanyan Zhao, Kazuhito Sato, Lijun Yao, Mamatha Serasanambati, Andrew Shinkle, Reyka G. Jayasinghe, Li Ding, Feng Chen. Spatial transcriptomic profiling of progression markers in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2025.
Abstract 1477: Circulating miR-125a-3p and miR-451a may be liquid biopsy biomarkers for the diagnosis of breast cancer
Authors: Hassan Yousefi, Steven C. Eastlack, Jordyn T Fong, Samuel C. Okpechi, Jovanny Zabaleta, Lyndsey R. Buckner, Donnalee N Trapani, Erin Sims, Alison McDaniel McDaniel, Heather Scuderi, Meredith A. Lakey, John T. Cole, Suresh K. Alahari
Journal: Cancer Research (2022)

Abstract Background: Breast cancer is the most prevalent female cancer. Emerging evidence suggests that the unique serum miRNAs can assist in the early detection and diagnosis of breast cancer. Cell-free circulating miRNAs (about 22 nucleotides) are potential diagnostic tools and minimally invasive biomarkers for breast cancer detection. This study aimed to identify specific microRNAs in the serum of patients with breast cancer, which may serve as promising diagnostic and prognostic biomarkers and therapeutic targets. Material and methods: Next-generation sequencing and quantitative real-time PCR (qRT-PCR) array analyses of microRNAs in sera from different subtypes of breast cancer patients and normal female individuals were performed. The differentially expressed microRNAs were verified in serum samples from 100 breast cancer patients. The predictive values of the selected microRNAs were statistically analyzed, determined by the correlation between microRNA expression and tumor parameters. Datasets were graphed using GraphPad Prism Software 8.0. and analysis was done using one-way ANOVA with unpaired two-tailed Student’s t-test. Result: High serum levels of miR-125a-3p and miR-451a were found to be associated with breast cancer tumor subtype, size, and lymph node metastasis. Further functional in vitro experiments and enrichment analysis showed that overexpression and knockdown of miR-451 might significantly affect tumorigenic signaling pathways in TNBC cells. Conclusion: Altogether, our data suggested that serum levels of microRNAs miR-125a-3p and miR-451a can potentially serve as liquid biopsy biomarkers in breast cancer. Citation Format: Hassan Yousefi, Steven C. Eastlack, Jordyn T Fong, Samuel C. Okpechi, Jovanny Zabaleta, Lyndsey R. Buckner, Donnalee N Trapani, Erin Sims, Alison McDaniel McDaniel, Heather Scuderi, Meredith A. Lakey, John T. Cole, Suresh K. Alahari. Circulating miR-125a-3p and miR-451a may be liquid biopsy biomarkers for the diagnosis of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1477.
Abstract SY22-02: Aneuploidy and 3D tissue rigidity
Authors: Dennis Discher
Journal: Cancer Research (2022)

Abstract Sequence differences between normal cells of the same person are increasingly evident (e.g. Yizhak Science 2019), and such somatic variations across different tissues increase from liquid to solid tissues, consistent with similar trends across liquid and solid tumors. Further analyses suggest changes increase with high levels of both replication-division (R=0.24) and the stiffness E of each tissue (R=0.6). Chromosome copy number gains and losses – aneuploidy – follow these trends, which prompted our hypothesis that stiff 3d microenvironments could increase aneuploidy of dividing cells moreso than less confining or microenvironments. We developed a method of live-cell monitoring of changes to chromosome copy numbers and used it to study diverse perturbations, particularly compressed mitosis seen in vivo. Many dividing cells die when squeezed, but rare stem cells and cancer cells show heritable loss of mono-allelic, GFP/RFP-tagged constitutive genes that function as Chromosome-reporters (ChReporters). Flattening spreads mitotic chromatin, favors chromosome mis-segregation, and increases ChReporter loss independent of an established spindle assembly checkpoint. Inhibiting the high level of Topoisomerase in such cells impedes chromosome compaction, division, and ChReporter loss, whereas the proposed tumor suppressor Myosin-IIA stabilizes chromatin against fragmentation, with knockdown increasing ChReporter loss. Solid human tumors and teratomas show similar ChReporter trends in mice, and single-cell-sequencing identifies rare chromosome changes exclusively in normal 3D-infiltrative cells while also relating specific chromosome losses to altered growth and motility. 3D rigidity thus gives rise to heritable aneuploidy as a mechanogenetic change. Citation Format: Dennis Discher. Aneuploidy and 3D tissue rigidity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY22-02.